There is substantial evidence that individuals may suffer from both mental disorders and physical disorders at the same time. Such is the case for depression and generalized anxiety and cardiovascular pathologies that include atherosclerosis-associated coronary heart disease and stroke. Therapeutic approaches that inhibit the enzyme 5-lipoxygenase (5-LOX) appear to be beneficial in atherosclerosis-related pathologies. This proposal hypothesizes that 5-LOX, an enzyme that metabolizes arachidonic acid into biologically active leukotrienes, could be a modifiable biological substrate involved in pathobiology of depression and anxiety. Recent work from this laboratory has behaviorally characterized transgenic 5-LOX-deficient mice. Compared to 5-LOX-normal controls, 5-LOX-deficient mice express less severe anxiety-like behaviors (i.e., plus maze and marble burying) and depression-like behaviors (forced swimming), suggesting that suppression of 5- LOX may be anxiolytic/antidepressant. Furthermore, a natural mutation in the 5-LOX gene, which generates an enzymatically inactive 5-LOX protein, appears to be responsible for the atherosclerosis-resistance phenotype in CAST mice. In the brain, 5-LOX is expressed in certain types of neurons and in the blood vessels; the predominant brain-type leukotrienes are cysLTs. In contrast to the known role of a 5-LOX in the cardiovascular system, the role of 5-LOX in brain functioning and behavior is poorly understood. Thus, the main objective of this R21 proposal is to fully characterize the behavioral consequences of 5-LOX deficiency in mice. Thus, we will: a) establish colonies of congenic 5-LOX-deficient transgenic mice and congenic CAST (CONG) 5-LOX mutant mice; b) characterize the behavior of the two congenic 5-LOX-deficient lines and their respective controls (using a battery of behavioral tests); c) investigate the behavioral consequences of treating mice with 5-LOX inhibitors. We expect this study to establish the role of the 5-LOX pathway in CNS functioning relevant to the pathobiology of anxiety/depression. If our hypothesis that 5-LOX contributes to "anxiogenic/depressed" behaviors is confirmed in experiments with 5-LOX-deficient mice, it would be important to consider 5-LOX gene polymorphism in clinical research on the pathobiology of depression and anxiety, and in conducting clinical studies with putative 5-LOX inhibitors. [unreadable] [unreadable]